Prostate cancer (PrCa) is the most commonly diagnosed cancer in men and the second leading cause of cancer deaths in males, following only lung cancer. Despite advances leading to more efficient detection, a small but significant number of patients present with advanced disease and/or disease that is hormone resistant or resistant to current therapeutics. Our proposal explores the novel application of small endogenous regulators of gene expression as a new class of therapeutics for prostate cancer. Within the last two decades there has been great interest in microRNAs (miRNAs), small, non-coding RNAs that have been initially identified as regulators of development, and have more recently been demonstrated to have a role in a number of cancers. miRNAs appear to regulate the expression of genes associated with early development and cancer by blocking the translation of target mRNA genes. Their levels are significantly altered in tumors, and their role in regulating the expression of key oncogenes and tumor suppressors suggests this differential expression may be involved in the pathophysiology of cancer. We hypothesize that dysregulated miRNAs are involved in maintaining cancer cell phenotypes and that correcting this dysregulation -- either by miRNA replacement with mimetic or ablation with antisense molecules -- should reverse these phenotypes. The goal of this proposal is to investigate promising miRNAs, delivery methods and delivery molecules that are effective therapies in animal models of human prostate cancer. We have substantial preliminary data that suggest a number of miRNAs may have therapeutic potential. In our investigations, we will test the therapeutic potential of miRNAs on several mouse models of human PrCa, including a model that mimics invasiveness and metastasis. Additionally we will evaluate stabilizing and release compounds that will allow systemic delivery of miRNA therapeutics. We believe these studies will help establish potent anti-cancer miRNAs that can be stabilized and eventually targeted to tumors, allowing delivery of these molecules into the bloodstream. PUBLIC HEALTH RELEVANCE: Advanced prostate cancer continues to be the second leading cause of cancer deaths in males, and is often resistant to conventional therapeutics. Our work may lead to the development of microRNA-based therapies that can be systemically administered and are highly and specifically active towards prostate cancer cells. This will result in a reduced incidence of death from prostate cancer.